Garbrecht et al., U.S. Pat. No.4,714,704, and Cohen et al., U.S. Pat. No. 4,713,384, describe dihydrolysergic acid esters of the following formula ##STR1##
The group R is primary or secondary C.sub.1-8 alkyl, CH.sub.2 --C.sub.2-4 alkenyl, C.sub.3-8 cycloalkyl, or C.sub.3-6 cycloalkyl substituted C.sub.1-5 primary or secondary alkyl, the total number of carbon atoms not exceeding 8, and the group R.sup.1 is C.sub.1 -C.sub.4 straight chain alkyl.
In Garbrecht et al., the group R.sup.2 is C.sub.1-3 alkyloxy C.sub.5-7 cycloalkyl, whereas, in Cohen et al., it is hydroxy C.sub.5-7 cycloalkyl. Highly preferred compounds are those in which R is isopropyl and R.sup.1 is methyl.
These compounds, all esters, are recognized to possess selective and highly potent antagonist activity at 5HT.sub.2 (5HT=serotonin) receptors upon intravenous or oral administration in rats.
Both of the foregoing classes of esters correspondingly demonstrate, as expected, high affinity in vitro for 5HT.sub.2 receptors. These properties are to be compared to the in vitro affinity of a corresponding free acid, 1-isopropyldihydrolysergic acid, i.e., in the foregoing formula, R is isopropyl, R.sup.1 is methyl, and R.sup.2 is hydrogen.
The latter compound is recognized to exhibit a relatively low level of affinity in vitro for 5HT.sub.2 receptors. It has been assumed, therefore, that the free acid would not be a likely candidate for use as an antagonist at 5HT.sub.2 receptors, and the literature suggests the utility of the free acid compounds solely as intermediates to active compounds. In this regard, see, e.g., the earlier cited Garbrecht et al. and Cohen et al., as well as Garbrecht, U.S. Pat. No. 3,580,916; Rucman, U.S. Pat. No. 4,230,859; and Hofmann et al., U.S. Pat. No. 3,249,617.
Surprisingly, however, we have recently discovered that 1-isopropyldihydrolysergic acid exhibits relatively high potency as a 5HT.sub.2 antagonist in vivo irrespective of its relatively low affinity for these receptors when measured in vitro. It is thus to the use of 1-isopropyldihydrolysergic acid as a 5HT.sub.2 antagonist, whether administered orally or by injection, that this invention is directed.